Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates.

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Kashiwazaki G, Bando T, Shinohara K, Minoshima M, Kumamoto H, Nishijima S, Sugiyama H

Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates.

Bioorg Med Chem. 2010 Apr 15;18(8):2887-93. doi: 10.1016/j.bmc.2010.03.011. Epub 2010 Mar 10.

PubMed ID

20350810 [ View in PubMed

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Abstract

We designed and synthesized human telomere alkylating N-methylpyrrole-N-methylimidazole (PI) polyamide conjugates (1-6). The C-type conjugates 1-3 possessed a chlorambucil moiety at the C terminus, whereas the N-type conjugates 4-6 had one of these moieties at the N terminus. The DNA alkylating activity of these conjugates was evaluated by high-resolution denaturing polyacrylamide gel electrophoresis using a 220bp DNA fragment containing the human telomere repeat sequence 5'-(GGGTTA)(4)-3'/5'-(TAACCC)(4)-3'. C-type conjugates are designed to alkylate the G-rich-strand-containing 5'-GGGTTA-3' and N-type conjugates were designed to alkylate the complementary C-rich strand-containing 5'-TAACCC-3' sequence. The difference between conjugates 1-3 and 4-6 lies in the linker region between the polyamide moiety and chlorambucil. Conjugates 1 and 4 efficiently alkylated the 5'-GGTTAGGGTTA-3' and 5'-CCCTAACCCTAA-3' sequences, respectively, by recognizing 11bp in the presence of distamycin A (Dist), in a heterotrimeric manner: one long alkylating polyamide conjugate (1-6) and two short partners (Dist).

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Chlorambucil	DNA	Nucleotide	Humans	Unknown	Cross-linking/alkylation	Details